The use of purine derivatives as anti-viral compounds is known. For example, U.S. Pat. No. 4,027,025 discloses 8-azapurine derivatives, such as 9-(2-hydroxyethoxymethyl)-8-azaguanine and 9-(2-benzoyloxyethoxymethyl)-8-azaguanine, as anti-viral compounds. U.S. Pat. No. 4,146,715 discloses 2-amido-9-(2-acyloxyethoxymethyl)hypoxanthines, and U.S. Pat. No. 4,199,574 discloses that 9-(2-hydroxyethoxymethyl) and related derivatives of certain 6-, and 2,6-substituted purines have anti-viral activity. U.S. Pat. Nos. 4,347,360 and 4,355,032 disclose that 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine (gancyclovir) has anti-viral activity and Colla et al., J. Med. Chem., 26, 602-604 (1983) and published European Patent Application No. 95 813 disclose esters or esters and ethers of acyclovir. European Patent Application Publication No. 85 424 discloses acyl derivatives of 9-(1,3-dihydroxy-2-propoxymethyl)guanine and U.S. Pat. No. 4,617,304 discloses thymidine kinase substrates having a 3-membered cycloalkyl group in the side chain of a purin-9-yl or pyrimidin-1-yl derivative, but disclose these compounds only as anti-viral agents, not as viral thymidine kinase inhibitors.
Inhibition of herpes simplex type I (HSV-1) thymidine kinase by certain 9-(hydroxyalkyl)- and 9-(hydroxyalkenyl)guanines has been disclosed in published EPO Application No. 146 516, but the antiviral activity of the compounds disclosed has been attributed to selective phosphorylation by the HSV thymidine kinase and subsequent inhibition of the viral DNA polymerase (A. Larsson et al, Antimicrob. Agents Chemother., 30, 598-605 (1986)).
Herpes simplex virus infections are currently best treated with acyclovir (ACV), which is a selective substrate for HSV thymidine kinase and (as the triphosphate) inhibits HSV DNA polymerase. ACV does not prevent establishment of latent infection, however, and for prophylaxis of recurrent infection, it must be administered daily in high doses. The maximum course of such treatment approved by the FDA is 6 months, after which the recurrences return to normal frequency.
Known antiviral agents, such as acyclovir, gancyclovir and BVDU, however, are susceptible to enzymatic phosphorylation in non-infected cells to a small extent and thus have an effect upon nucleotide pool sizes and, by means of DNA polymerase, can be incorporated into DNA, thus raising mutagenicity hazards.
It is believed that non-TK-substrates, which might not possess chemotherapeutic efficacy, would have potential in the prevention of viral reactivation from latency or in the abolition of viral latency itself.
It was therefore an object of the present invention to identify novel, viral thymidine kinase (TK) inhibitory compounds which are not TK-substrates. Another object was to identify compounds which have utility and particularly safety in the treatment of specific members of the herpes group (i.e., herpes simplex, types 1 and 2, and varicella zoster), which express their own thymidine kinase. A further object of the present invention was to identify pharmaceutical formulations for the effective administration of the novel compounds of the invention. Still another object is to provide methods for the preparation of the novel compounds of the present invention.